Transcript Categories of disease

Human Disease
(Part 1 of 2)
Monday, November 10, 2003
Introduction to Bioinformatics
Johns Hopkins School of Medicine
ME:440.714
J. Pevsner
[email protected]
Copyright notice
Many of the images in this powerpoint presentation
are from Bioinformatics and Functional Genomics
by Jonathan Pevsner (ISBN 0-471-21004-8).
Copyright © 2003 by John Wiley & Sons, Inc.
These images and materials may not be used
without permission from the publisher. We welcome
instructors to use these powerpoints for educational
purposes, but please acknowledge the source.
The book has a homepage at http://www.bioinfbook.org
Including hyperlinks to the book chapters.
Schedule
Today: human disease (last lecture)
Wednesday Nov 20: final exam, in class
Find-a-gene project due Wednesday
References
Barton Childs and David Valle “Genetics, Biology
and Disease” Annu Rev. Genomics Hum. Genet.
2000, 01:1-19.
Nature and Science human genome issues have
articles from Valle, McKusick & colleagues.
Jimenez-Sanchez G, Childs B, Valle D. Human disease genes.
Nature 2001 Feb 15;409(6822):853-5.
Peltonen L, McKusick VA. Genomics and medicine. Dissecting human
disease in the postgenomic era. Science 2001 Feb 16;291(5507):1224-9.
Life is a relationship between molecules, not a property of any one molecule.
So is therefore disease, which endangers life. While there are molecular diseases,
there are no diseased molecules. At the level of the molecules we find only variations
in structure and physicochemical properties. Likewise, at that level we rarely detect
any criterion by virtue of which to place a given molecule “higher” or “lower” on the
evolutionary scale. Human hemoglobin, although different to some extent from that
of the horse (Braunitzer and Matsuda, 1961), appears in no way more highly
organized. Molecular disease and evolution are realities belonging to superior
levels of biological integration. There they are found to be closely linked, with no
sharp borderline between them. The mechanism of molecular disease represents one
element of the mechanism of evolution. Even subjectively the two phenomena of
disease and evolution may at times lead to identical experiences. The appearance
of the concept of good and evil, interpreted by man as his painful expulsion from
Paradise, was probably a molecular disease that turned out to be evolution.
Subjectively, to evolve must most often have amounted to suffering from a disease.
And these diseases were of course molecular.
Emile Zuckerkandl and Linus Pauling (1962)
Page 647
Human disease: a consequence of variation
Genetic variation is responsible for the adaptive
changes that underlie evolution.
Some changes improve the fitness of a species.
Other changes are maladaptive.
For the individual in a species, these maladaptive
changes represent disease.
Molecular perspective: mutation and variation
Medical perspective: pathological condition
Page 647
Why is there such a diversity of diseases?
-- many regions of the genome may be affected
-- there are many mechanisms of mutation
-- genes and gene products interact with their
molecular environments
-- an individual interacts with the environment
in ways that may promote disease
Page 648
Outline
Overview of human disease (classification)
Molecular level
DNA, RNA, protein
Systems level
Organellar, systems disease databases
Organismal level
Clinical phenotypes
Animal models
Disease organizations
Bioinformatics perspectives on disease
The field of bioinformatics involves the use of computer
algorithms and databases to study genes, genomes,
and proteins.
• DNA databases offer the reference sequences with which to
compare normal sequences and those associated with disease
• Physical and genetic maps are used in gene-finding studies
• Protein structure studies allow study of effects of mutation
• Many functional genomics approaches applied to genes
• Insight into human disease genes is provided through
the study of orthologs
Page 649
Perspectives on disease
Medicine: diagnosis, treatment, prognosis, prevention
of disease
Genetics: understanding the origin and expression
of individual human uniqueness
Genomics: identifying and characterizing genes
and their arrangement in chromosomes
Bioinformatics: the use of computer algorithms and
computer databases to study genes, genomes,
and proteins.
Page 649
Outline
Overview of human disease (classification)
Molecular level
DNA (OMIM, SNP, LSDB), RNA, protein
Systems level
Organellar, systems disease databases
Organismal level
Clinical phenotypes
Animal models
Disease organizations
Archibald Garrod’s view of disease
Sir Archibald Garrod (1857-1936) made important
contributions to our understanding of disease.
In a 1902 paper (see page 650 for URL of on-line version),
he described the rare inherited disorder alkaptonuria.
He argued that variations in metabolic processes between
individuals might include disease-causing changes.
Such traits are inherited according to Mendel’s laws.
In his book Inborn Errors of Metabolism (1909),
Garrod discusses how the disease phenotype reflects
the chemical individuality of the each person.
Page 650
Archibald Garrod’s view of disease
In a second book, Inborn Factors in Disease (1931),
Garrod discusses how chemical individuality predisposes
us to various diseases (whether the disease is inherited,
caused by infection, or by an environmental agent).
Every disease process is affected by both internal
and external forces.
Page 651
Categories of disease
We can consider five main categories of human disease.
Page 652
Categories of disease
Single gene disorders
rare
Complex disorders
common
Chromosomal disorders
very common
Infectious disease
most common
Environmental disease
common
Page 652
Categories of disease
Single gene disorders
autosomal dominant
autosomal recessive
X-linked recessive
rare
Complex disorders
congenital anomalies
CNS
cardiovascular
common
Chromosomal disorders
very common
Infectious disease
most common
Environmental disease
common
Page 652
Categories of disease
Single gene disorders
autosomal dominant
autosomal recessive
X-linked recessive
rare
multigenic
pathophysiology
Complex disorders
congenital anomalies
CNS
cardiovascular
common
multigenic
Chromosomal disorders
common
multigenic
Infectious disease
common
multigenic
Environmental disease
common
multigenic
Categories of disease
Example:
Lead poisoning is an environmental disease. It is common
(about 9% of US children have high blood levels).
But two children exposed to the same dose of lead
may have entirely different phenotypes.
This susceptibility has a genetic basis.
Conclusion: genes affect susceptibility to environmental
insults, and infectious disease. Even single-gene disorders
involve many genes in their phenotypic expression.
Page 653
Classification of disease
There are several approaches to disease classification that
are relevant to our bioinformatics perspective of disease.
(Also, the field of bioinformatics [health sciences informatics]
is specifically involved in disease classification.)
Death rankings
Disability-adjusted life years (DALYs)
Classification systems:
-- International Statistical Classification of Diseases
and Related Health Problems (ICD-9 and ICD-10)
-- National Library of Medicine (MeSH terms)
Page 653
Classification of disease
Leading causes of death (U.S., 1999)
number of
Rank Cause
deaths
1
heart disease
725,192
2
malignant neoplasm
549,192
3
cerebrovascular disease 167,366
4
chronic lower respiratory 124,181
5
accidents
97,860
6
diabetes mellitus
68,399
7
influenza, pneumonia
63,730
8
Alzheimer’s disease
44,536
9
nephritis & related
35,525
10
septicemia
30,680
all other
2,391,399
Source: National Vital Statistics Reports 49(11):1-87, 2001.
% total
deaths
30.3
23.0
7.0
5.2
4.1
2.9
2.7
1.9
1.5
1.3
20.2
Page 653
The global burden of disease
See p. 654 for URL
Fig. 18.3
Page 654
See p. 654 for URL
Fig. 18.4
Page 654
Classification of disease
The International Statistical Classification of Diseases and
Related Health Problems (ICD) is the main disease
classification system used in health care. Examples of
categories are:
1. Infectious and parastic disease
2. Neoplasms
3. Endocrine, nutritional, and metabolic diseases…
4. Diseases of the blood and blood-forming organs
5. Mental disorders
6. Diseases of the nervous system and sense organs
7. Diseases of the circulatory system
8. Diseases of the respiratory system
9. Diseases of the digestive system
See http://www.who.int/whosis/icd10/
Page 655
The National Library of Medicine (NLM) includes
Medical Subject Heading (MeSH) terms for disease
Fig. 18.5
Page 656
The National Library of Medicine (NLM) includes
Medical Subject Heading (MeSH) terms for disease
Fig. 18.5
Page 656
The National Library of Medicine (NLM) includes
Medical Subject Heading (MeSH) terms for disease
Fig. 18.5
Page 656
Monogenic (single gene) disorders
Previously, a large distinction was made between
monogenic (single gene) and polygenic (complex) disorders.
They are now seen to be more on a continuum.
We may define a single-gene disorder as a disorder that
is caused primarily by mutation(s) in a single gene.
However, as we will see below, all monogenic disorders
involve many genes.
Page 655
Monogenic (single gene) disorders
Autosomal dominant
BRCA1, BRCA2
Huntington chorea
Tuberous sclerosis
Autosomal recessive
Albinism
Sickle cell anemia
Cystic fibrosis
Phenylketonuria
X-linked
Hemophilia A
Rett Syndrome
Fragile X Syndrome
1:1000
1:2,500
1:15,000
1:10,000
1:655 (U.S. Afr.Am)
1:2,500 (Europeans)
1:12,000
1:10,000 (males)
1:10,000 (females)
Table 18.4
1:1,250 (males)
Page 656
Monogenic (single gene) disorders
Sickle cell anemia is an example of a single gene disorder.
It is caused by mutations in beta globin (HBB). We saw
that the E6V mutation is very common (Chapter 9).
This mutation causes hemoglobin molecules (a2b2) to
aggregate, giving red blood cells a sickled appearance.
This single gene disorder is unusually prevalent because
the heterozygous state confers protection to those
exposed to the malaria parasite.
You can read Linus Pauling’s 1949 article describing the
abnormal electrophoretic mobility of HBB on-line at
http://profiles.nlm.nih.gov/MM/B/B/R/L/
Page 657
A monogenic disorder: Rett Syndrome
Rett syndrome (RTT) is another example of a single gene
disorder. We will discuss the following aspects:
Clinical presentation
Neurobiology
Gene defect: MECP2, a transcriptional repressor (Xq28)
OMIM entry
Locus-specific database entry
Single nucleotide polymorphisms (SNPs)
Box 18.2
Page 658
Rett Syndrome: Clinical Presentation
Normal pre- and perinatal development
Neurocognitive regression
Deceleration of head and brain growth
Loss of speech + social skills (autistic)
Loss of purposeful hand movements
Truncal ataxia
Repetitive hand movements
Seizures
Box 18.2
Page 658
Rett Syndrome: Neurobiology
• Decreased Total Brain Volume
• Reduced Cortical Thickness
• Nigrostriatal Pathology
• Basal Forebrain Cholinergic System
• Glutamatergic Abnormalities
• Disruption of Neuronal Markers in olfactory epithelium
Box 18.2
Page 658
Rett Syndrome: Genetics
• Affects only females (~1/15,000)
• X-linked male-lethal?
• “Genetic Lethality”
• >99% of cases are sporadic
• Twins: MZ - 7/8 DZ - 2/13
• Mother - daughter pair
• X exclusion mapping: Xq28
• Linkage analysis: Xq28
Box 18.2
Page 658
Mutations in MECP2 cause Rett Syndrome
Rett Syndrome is Caused by Mutations in X-linked MECP2,
Encoding Methyl-CpG-Binding Protein
R.E. Amir et al. (Nature Genetics October 1, 1999)
Transcriptional
repression domain
Methyl CpG
binding domain
Box 18.2
Page 658
Overview of MeCP2 Function
Active
Transcription
methylation
Transcriptional
Repression
MeCP2
Histone
mSin3a
Deacetyl
Box 18.2
Page 658
Disease principles highlighted by RTT
-- sex ratio (almost exclusively females) is likely caused
by a high mutation rate in fathers. (An alternative
explanation would be male lethality in utero.)
XY
XY
XX
XX
Box 18.2
Page 658
Disease principles highlighted by RTT
-- phenotype in males (severe neonatal encephalopathy,
often fatal) does not resemble that of females
-- females may be spared a more severe phenotype
because of random X chromosome inactivation.
In all females, each cell chooses to express either
the maternal or paternal X chromosome, early in life.
Thus RTT females are a mosaic of cells expressing
normal and mutated copies of MECP2.
-- X-inactivation patterns in females are normally about
50-50. However they may be skewed 99-1, allowing a
female to be a carrier. Several females have given
birth to affected daughters.
Page 658
Disease principles highlighted by RTT
-- an identical mutation in MECP2 in two females may
result in extremely different phenotypes. There are
two main explanations:
[1] Additional, modifier genes may affect the disease
process. This is seen for sickle cell anemia and
for many other single gene disorders.
[2] Many epigenetic factors may influence the
clinical phenotype. In RTT, the methylation
status of genomic DNA could be important.
Skewed X-inactivation can cause even identical
twins to exhibit different phenotypes.
Page 658
This lecture continues in part 2
with a discussion of OMIM…
http://pevsnerlab.kennedykrieger.org/ppts/lecture_bioinf_ch18_part2.ppt